AMP-Activated Protein Kinase α1 Regulates Cardiac Gap Junction Protein Connexin 43 and Electrical Remodeling Following Pressure Overload

Abstract

Background/Aims: Adenosine 5'-monophosphate (AMP)-activated protein kinase (Ampk) modulates a wide array of cellular functions and regulates various ion channels and transporters. In failing human hearts an increased Ampkα1 activity was observed. The present study aimed to uncover the impact of Ampkα1 on cardiac electrical remodeling. Methods: Gene-targeted mice lacking functional Ampkα1 (Ampkα1-/-) and corresponding wild-type mice were exposed to pressure overload by “transverse aortic constriction” (TAC). In vivo electrophysiology was performed with a single catheter technique, myocardial conduction velocities and conduction characteristics investigated in isolated hearts, transcript levels quantified by RT-PCR and protein abundance determined by Western blotting. Moreover, connexin 43 (Cx43) was expressed in Xenopus oocytes with or without coexpression of wild-type or mutant AMPK and Cx43 protein abundance quantified utilizing confocal microscopy. Results: TAC treatment increased Ampkα1 protein expression in cardiac tissue from wild-type mice. TAC further increased left ventricular conduction inhomogeneity and triggered conduction blocks, effects blunted in the Ampkα1^-/- mice. TAC treatment decreased Cx43 protein abundance in cardiac tissue, an effect significantly blunted in the Ampkα1^-/- mice. TAC treatment did not modify Cx43 mRNA levels but increased ubiquitination of Cx43 protein, an effect mitigated by Ampkα1 deficiency. As shown in Xenopus oocytes, Cx43 cell membrane protein abundance was significantly downregulated by wild-type AMPK^WT and constitutively active AMPK^γR70Q, but not by catalytically inactive AMPK^αK45R. Conclusion: Ampkα1 stimulates ubiquitination of the gap junction protein Cx43, thereby contributing to gap junction remodeling following pressure overload.

Baicalin Attenuates Cardiac Dysfunction and Myocardial Remodeling in a Chronic Pressure-Overload Mice Model

“…We measured the left ventricular end-diastolic diameter (LVEDD), and left ventricular end-systolic diameter (LVESD), interventricular septal thickness in diastole (IVSd) and in systole (IVSs) in M-mode. Left ventricular fractional shortening (FS) and ejection fraction (EF) were calculated as previously described [20]. All of these parameters were obtained from at least three beats and averaged subsequently.…”

Irregular rhythm and atrial metabolism are key for the evolution of proarrhythmic atrial remodeling in atrial fibrillation

“…Since the present work did not validate whether AMPK inhibition reduces apoptosis under these experimental conditions, AMPK activation might be an adaptive response to AF, with the apoptosis resulting from other pathways activated during AF. On the other hand, AMPK activation can also stimulate ubiquitination of connexin-43, producing conduction heterogeneities that could promote AF maintenance/progression [1]. Taken together, these data suggest that both increased and decreased AMPK activation may have multiple pro-and antiarrhythmic roles.…”

Novel Functional Role of Heat Shock Protein 90 in Mitochondrial Connexin 43-Mediated Hypoxic Postconditioning

“…Connexin 43 (Cx43) is the predominant protein forming gap junctions in ventricular myocardium and is essential for intercellular electrical conduction and cell survival in mammals [11]. Apart from its localization at the sarcolemma, Cx43 is also expressed in mitochondria in cardiomyocytes [12].…”